1. Field of the Invention
The present invention relates generally to the field of cancer biology. More particularly, it concerns HER3 targeting monoclonal antibodies for the treatment and detection of cancer.
2. Description of Related Art
The epidermal growth factor receptor (EGFR) family (ErbB/HER) consists of four known members: EGFR (HER1, erbB-1), HER2 (erbB-2), HER3 (erbB-3), and HER4 (erbB-4). Each receptor protein has the same basic structure, consisting of an extracellular amino-terminal domain, a single transmembrane spanning sequence and an intracellular cytoplasmic domain. ErbB signaling has a complex network with more than 11 interacting ligands for distinct binding specificities and activation of signaling pathways. The complex contents and interactions of HER receptors and ligands provide a great potential for significant signal diversification.
Growing evidence indicates that HER3 plays important role in the resistance mechanisms of HER targeting therapeutics including both small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and lapatinib, and HER family receptor targeting monoclonal antibodies, such as trastuzumab, cetuximab, panitumumab and pertuzumab. Heregulin/Neuregulin (NRG) is a member of a complex ligand family interacting with HER3 and HER4. Neuregulin binding activates ErbB3 and leads to formation of heterodimeric receptor complexes and activation of down stream signaling of HER3 through both PI3K/AKT and Ras/Raf/MAPK pathways. Therefore, HER3-binding monoclonal antibodies to block neuregulin binding have the potential to block HER3 signaling and inhibit cancer cell proliferation.